Heart failure (HF) is major health problem in the United States (U.S.) and elsewhere. In the U.S., HF affects over 5 million people with approximately half a million new cases occurring each year. HF is the leading cause of hospitalizations in people over 65 years in age. HF has many potential causes and diverse clinical features. Symptoms of heart failure can include dyspnea during activity or at rest, cough, rapid weight gain, swelling in ankles, legs and abdomen, dizziness, fatigue and weakness, rapid or irregular heartbeats, nausea, palpitations, and chest pains.
About half of heart failure subjects have heart failure with preserved ejection fraction (HFPEF). Distinct from traditional HF, i.e., heart failure with reduced ejection fraction (HFREF) in which the ventricle has difficulty pumping, subjects with HFPEF show declined performance of heart ventricle, not at the time of contraction, but during the phase of diastole. HFPEF subjects show normal ejection fraction of blood pumped out of the ventricle, but the heart muscle does not quickly relax to allow efficient filling of blood returning from the body. Morbidity and mortality of HFPEF are similar to traditional HF; however, therapies that benefit traditional HF are not effective in treating or preventing HFPEF. Subjects with HFPEF have an ejection fraction of ≥40%, ≥45%, or ≥50% depending on which definition is chosen from the literature. On the other hand, subjects with HFREF have an ejection fraction of either ≤35% or ≤40% depending on which definition and guidelines are used. For ease of simplicity, and not to be limiting in any way, HFPEF can be considered as having an ejection fraction ≥40% and HFREF can be considered as having an ejection fraction ≤40%.
Other names for the two primary clinical subsets of HF are diastolic heart failure (DHF) and systolic heart failure (SHF). SHF, which is also known as heart failure with reduced ejection fraction (HFREF) involves an abnormality of the heart resulting in failure of the heart to pump blood at a rate needed for metabolizing tissues at rest and/or during exertion. DHF, also known as heart failure with preserved ejection fraction (HFPEF), is a clinical syndrome with symptoms and signs of HF, a preserved ejection fraction and abnormal diastolic function. The clinical manifestations of HFREF and HFPEF have distinct differences in risk factors, subject characteristics, and pathophysiology. Moreover, medications proven effective in HFREF have not been found to be effective in HFPEF. At present, there are no approved treatments for HFPEF.
In HFREF, medications such as beta-blockers, ace-inhibitors, angiotensin receptor blockers, isosorbide dinitrate, hydralazine, aldosterone inhibitors, and angiotensin receptor neprilysin inhibitors have been shown to provide benefit. However, these medications have not shown to be beneficial in subjects with HFPEF, and are not approved therapies for HFPEF.
Given that there are currently no approved treatments to improve survival in HFPEF, there remains, therefore, a real need in the treatment of HFPEF for a product that can improve morbidity and mortality of subjects with HFPEF.
The present disclosure addresses these needs in subjects with HFPEF, as well as in subjects at risk of developing HFPEF, due to conditions including but not limited to hypertension, diabetes, COPD, atrial fibrillation, obesity, or ischemic heart disease.
Fumaric acid esters (FAEs) are approved in Germany for the treatment of psoriasis, are being evaluated in the United States for the treatment of psoriasis and multiple sclerosis, and have been proposed for use in treating a number of immunological, autoimmune, and inflammatory diseases and conditions.
FAEs and other fumaric acid derivatives have been proposed for use in treating a wide-variety of diseases and conditions involving immunological, autoimmune, and/or inflammatory processes including psoriasis (Joshi and Strebel, WO 1999/49858; U.S. Pat. No. 6,277,882; Mrowietz and Asadullah, Trends Mol Med 2005, 111(1), 43-48; and Yazdi and Mrowietz, Clinics Dermatology 2008, 26, 522-526); asthma and chronic obstructive pulmonary diseases (Joshi et al., WO 2005/023241 and US 2007/0027076); mitochondrial and neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease, retinopathia pigmentosa and mitochondrial encephalomyopathy (Joshi and Strebel, WO 2002/055063, US 2006/0205659, U.S. Pat. Nos. 6,509,376, 6,858,750, and 7,157,423); transplantation (Joshi and Strebel, WO 2002/055063, US 2006/0205659, U.S. Pat. Nos. 6,359,003, 6,509,376, and 7,157,423; and Lehmann et al., Arch Dermatol Res 2002, 294, 399-404); autoimmune diseases (Joshi and Strebel, WO 2002/055063, U.S. Pat. Nos. 6,509,376, 7,157,423, and 2006/0205659) including multiple sclerosis (MS) (Joshi and Strebel, WO 1998/52549 and U.S. Pat. No. 6,436,992; Went and Lieberburg, US 2008/0089896; Schimrigk et al., Eur J Neurology 2006, 13, 604-610; and Schilling et al., Clin Experimental Immunology 2006, 145, 101-107); ischemia and reperfusion injury (Joshi et al., US 2007/0027076); AGE-induced genome damage (Heidland, WO 2005/027899); inflammatory bowel diseases such as Crohn's disease and ulcerative colitis; arthritis; and others (Nilsson et al., WO 2006/037342 and Nilsson and Muller, WO 2007/042034).
FUMADERM®, an enteric coated tablet containing a salt mixture of monoethyl fumarate and dimethyl fumarate (DMF) which is rapidly hydrolyzed to monomethyl fumarate, regarded as the main bioactive metabolite, was approved in Germany in 1994 for the treatment of psoriasis. FUMADERM® is dosed three times a day (TID) with 1-2 grams/day administered for the treatment of psoriasis. FUMADERM® exhibits a high degree of intersubject variability with respect to drug absorption and food strongly reduces bioavailability. Absorption is thought to occur in the small intestine with peak levels achieved 5-6 hours after oral administration. Significant side effects occur in 70-90% of subjects (Brewer and Rogers, Clin Expt'l Dermatology 2007, 32, 246-49; and Hoefnagel et al., Br J Dermatology 2003, 149, 363-369). Side effects of current FAE therapy include gastrointestinal upset including nausea, vomiting, diarrhea and/or transient flushing of the skin.
Dimethyl fumarate (DMF) is the active component of BG-12, also known as Tecfidera®, studied for the treatment of relapsing-remitting MS (RRMS). In a Phase IIb RRMS study, BG-12 significantly reduced gadolinium-enhancing brain lesions. In preclinical studies, DMF administration has been shown to inhibit central nervous system (CNS) inflammation in murine and rat EAE. It has also been found that DMF can inhibit astrogliosis and microglial activations associated with EAE. See, e.g., US Published Application No. 2012/0165404.
Despite its benefits, dimethyl fumarate is also associated with significant drawbacks. For example, dimethyl fumarate is known to cause side effects upon oral administration, such as flushing and gastrointestinal events including, nausea, diarrhea, and/or upper abdominal pain in subjects. See, e.g., Gold et al., N. Eng. J. Med., 2012, 367(12), 1098-1107. Dimethyl fumarate is dosed two times a day (BID) or TID with a total daily dose of about 480 mg to about 1 gram or more.
Further, in the use of a drug for long-term therapy it is desirable that the drug be formulated so that it is suitable for once- or twice-daily administration to aid subject compliance. A dosing frequency of once-daily or less is even more desirable.
Another problem with long-term therapy is the requirement of determining an optimum dose, which can be tolerated by the subject. If such a dose is not determined this can lead to a diminution in the effectiveness of the drug being administered.
Accordingly, it is an object of the present disclosure to provide compositions, which are suitable for long-term administration for subjects in need of therapy of heart failure disease, including heart failure with preserved ejection fraction.
It is a further object of the present disclosure to provide the use of a pharmaceutical active agent in a manner, which enables one to achieve a tolerable steady state level for the drug in a subject being treated therewith.
Because of the disadvantages of dimethyl fumarate described above, there continues to be a need to decrease the dosing frequency, reduce side-effects and/or improve the physicochemical properties associated with DMF. There remains, therefore, a real need in the treatment of certain conditions for a product that retains the pharmacological advantages of DMF but overcomes its flaws in formulation and/or adverse effects upon administration. The present disclosure addresses these needs in subjects with heart failure disease.